This proposal will develop novel preclinical methodology for evaluating the relative abuse liability of electronic cigarettes (ECs) in adolescents, and test the hypothesis that non-nicotine constituents contribute to EC abuse liability in this population. New tobacco products regulated by the Food and Drug Administration (FDA) Center for Tobacco Products (CTP) must undergo abuse liability testing prior to marketing. The FDA CTP has announced its intention to regulate ECs, which have surpassed tobacco cigarettes as the primary tobacco product used by adolescents despite their unknown health consequences. Development of appropriate methodology for evaluating the relative abuse liability of ECs in adolescents is urgently needed for informing FDA CTP policy regarding these products and for anticipating their impact on public health. Animal models are needed for this process, as they allow for examination of issues that are difficult or impossible to study experimentally in humans (e.g., initiation of tobacco use in adolescents). Current animal models of tobacco abuse that only examine nicotine alone and/or other isolated tobacco constituents may not be sufficient for evaluating tobacco products such as ECs because a) other compounds in tobacco products may contribute (positively or negatively) to tobacco abuse, and b) it is the interaction or summation of all the compounds in a tobacco product that determines its actual abuse liability. Therefore, new preclinical models involving exposure to a mixture of nicotine and other constituents derived directly from ECs may be necessary for an accurate assessment of the abuse liability of these products. To this end, this project will compare the abuse-related effects of nicotine alone versus nicotine dose-equivalent concentrations of EC aerosol extracts in adolescent rats. Because some non-nicotine constituents present in EC aerosol (e.g., minor alkaloids) can mimic or enhance nicotine's addiction-related effects, the general hypothesis is that extracts will have greater abuse liability than equivalent doses of nicotine alone. Consistent with this hypothesis, our preliminary data indicate that delivery of nicotine in EC refill liquid o aerosol extract attenuates its aversive effects. Because nicotine's aversive effects limit its intake, this effect could increase EC consumption. To further test our hypothesis, Aim 1 will compare the reinforcing effects of nicotine alone and extracts as measured by acquisition of i.v. self-administration. A behavioral economic approach will also be used to compare the reinforcing efficacy of these formulations during a progressive reduction in nicotine unit dose. Aim 2 will compare formulations in terms of their aversive effects as measured using conditioned taste aversion. The methodology established in these studies will be useful for anticipating the relative abuse liability of ECs, as well as for modeling FDA CTP-mandated changes in product standards for nicotine or other constituents in ECs. This project also directly addresses several FDA CTP interest areas including EC initiation, use, and dependence, and the impact of tobacco product characteristics (e.g., constituents) on initiation in adolescents.